New strategies for trial design and biomarker discovery Emilio Bria U.O.C. di Oncologia Medica d.U....

New strategies for trial design and biomarker

discoveryEmilio BriaU.O.C. di Oncologia Medica d.U.Azienda Ospedaliera Universitaria IntegrataPoliclinico ‘G.B. Rossi’ – VERONAemilio.bria@ospedaleuniverona.it

Roma, 18 Maggio 2012

Cancer that cannot be found• Died from bladder

cancer in 1978,– NEGATIVE

CITOLOGY, haematuria since at least 1967

– having been diagnosed with microinvasive bladder cancer in 1973

– frankly invasive disease in 1976.

• P53 mutation

• P53 mutation

• P53 mutation

Hubert Humphrey, US Vice President (1964–1968)

Hypothesis: p53mut as biomarker of ‘subclinical’ cancer

‘The Ideal’ Medicine

Medicine forThe Single Individual

Medicine forThe population

Knolewdge of biological targets

May 18st, Why this issue?

• ‘New age’ of medical oncology● Biological advances and/or discovery● New available techniques● Big amount of knowledge from our basic science

friends (……those ‘scientists’….)

• Many new drugs available● With almost unknown mechanism of action

‘The Ideal’ CurveCured

Patients

How was that?

Sign. detrimental No difference

‘Negligible benefit‘ Small benefit

Can we ‘perform’ better with these curves?

Biomarkers’ Driven vs Unselection Approach• Three RCTs (1987 patients) • Attrition rate 45% (range 20-60%)

PatientsExpected survival

differenceRequired

events

‘Unselected’ HR 0.90 (0.80-1.00) 2382‘Biomarker-selected’

HR 0.60 (0.40-0.89) 126

Interaction: p=0.025Power 80%, alpha-error 0.05

Yes……….we could!

Heterogeneity: p=0.025

New drugs in development for cancer treatment

PhRMA report 2009 – The Challenge of Numbers

PM Lo Russo et al., Clin Cancer Res 2010

Success rates from 1-in-human to registration for ten large pharma companies in the US/Europe [1991–2000].

The challenge of anticancer drug development

● Time- and resource-intensive process • >800 million $ to bring a new oncology drug to

market!

Potential effects of personalised medicine onpharmaceutical industry drug development

What issues for clinical trial design?

• New methodologies:● More ‘targets’ (more or less)● More patient’ (sub-)groups

• Re-assessment of end-points:● Is response adequate for phase II?● Is the phase II fashion a reasonable approach?● Is the phase III trial always required (of course, a provocative

question)?• If yes, which kind of RCTs?

New ‘Smart’ Drugs:Always ‘Targeted’?

• Un-Targeted design● Randomized comparison without measuring the

‘classifier’• Example: ECOG 4599-Beva

• Targeted design● Randomize only test + patients

• Example: EURTAC (Erlotinib vs CT – EGFR-M+)

Modified - Courtesy of Simon R, 2008

• But something is moving on……..● Association between VEGF genotype and median OS as well

as grade 3 or 4 hypertension, Schneider [ECOG 2100 update], JCO Oct 2008

How Trastuzumab Entered the market?

Buyse, ASCO 2005

Simulation of Randomized Phase III Trial in which 25% of active patients

show a treatment effect

What if Trastuzumab were developed per conventional approach in all comers

Simulation of Randomized Phase III Trial in which 100% of active

patients show a treatment effect

Modified by Gianni, 2011

........The plot thickens!

‘Average’ Drug Development

1 yr

1-2 yrs

2+ yrs

At least 5 yrs with multicenter, cooperative trials

Courtesy of Billingham C, 2008

• After preclinical, in the 1-3 yrs of drug development, you can:● Easily control drug effect● Monitor either biological and clinical action● Identify the ‘REAL’ target (if present!)

• When the drug enters phase III, only early stopping can be applied (with all related concerns….)

The Role of ‘Early’ phases (I-II) is CRUCIAL !

‘Early’ phases (II): Limitations

12

Courtesy of Billingham C, 2008

• Studies that met the criteria for appropriate citation of

prior data were significantly less likely to reject the null

(33%) than those cited that did not meet the criteria

(85%) P = 0.006

1

• Predictors of success at multivariate analysis:– Positive Phase II

results (p=.027)– Pharma

company-sponsored (p=.014)

– Short interval between Phase II and III publication (p<.001)

– Multi-institutional trials (p=.016)

Use of PFS/TTP As Primary End Point [%] in RCTs (BC, CRC, NSCLC)Major Journals [1975-2009]

1. Conversely to Classical cytotoxics, Targeted agents selectively hit a specific molecule/enzyme

• their functional/clinical effects are directly related to the level of target inhibition

2. Targeted agents are ‘cytostatic’ in nature: • they will slow down growth, but seldom shrink pre-

existing tumor masses

Targeted Agents – ’MYTHS’

Modified - Courtesy of Milella M, ESMO 2008

‘Targeted’ agents, particularly ATP-competitive kinase inhibitors, frequently hit multiple targets

Modified - Courtesy of Milella M, ESMO 2008

1. Conversely to Classical cytotoxics, Targeted agents selectively hit a specific molecule/enzyme

• their functional/clinical effects are directly related to the level of target inhibition

2. Targeted agents are ‘cytostatic’ in nature: • they will slow down growth, but seldom shrink pre-

existing tumor masses

Modified - Courtesy of Milella M, ESMO 2008

Targeted Agents – ’MYTHS’

TRUE, but see PFS & OS!

Stupid and Smart CancersSmart Cancer

Multiple mutational drivers

Large Mutational load

Multi-targeted therapy required

Resistance common, early

Stupid Cancer

Single Dominant Mutation

Small Mutational Load

Monotherapy is effective

Resistance rare, late, same pathway

Adapted from G. Sledge, ASCO 2011

2

Courtesy of Billingham C, 2008Ndr: #1 issue is still there!

Medical Oncology Clinical Research Scenario

• The phase II randomized should:● So far:

• Test EXPERIMENTAL drugs/combos, and pick the winner for further phase III

• Be aimed to safety and activity (i.e. response rates)

• DO NOT USE survival end-points• NEVER compare treatment arms

● From now on (with targeted agents):

• ?????????????????????

What is less dangerous?(…to obtain more accurate results from early studies with

targeted agents)

SINGLE-ARM Phase II

Response as end-point

Uncontrolled

MULTIPLE-ARM Phase II RandomSurvival as end-point

Controlled

Targeted Agents – Phase II

• Uncontrolled Design (‘Classical’ Phase II)●High efficiency in identifying non-active drugs

(high NPV) ●Low efficiency in selecting the best

challengers for phase III (low PPV)

Modified - Courtesy of Perrone F, AIOM Conf. 2008

• Controlled Design (‘Comparative’ Phase II Randomized) ● Increase PPV●Should be (must be) conducted with ‘relaxed’

statistical criteria (i.e. alfa one-sided = 0.20)●MUST be followed (if positive) by a classical

phase III with traditional rules

Modified - Courtesy of Perrone F, AIOM Conf. 2008

Targeted Agents – Phase II

Moving to Phase III design

• Many cancer treatments benefit only a small proportion of the patients to which they are administered

• By targeting treatment to the right patients1. Treated patients benefit2. Treatment more cost-effective for society3. More informative and successful clinical trials

Modified - Courtesy of Simon R, 2008

Attrition rates in biomarker analysis: the IPASS study

HIGH LOW

Attrition rates in biomarker analysis: the IPASS study

• EGFR mutation status appears to be a good prognostic factor, but a weak predictive factor for survival (G. Clark)

Do never forget the prognostic effect!

Does ‘control’ actually work?Does ‘control’ actually work?

Do we all still trust ‘retrospective’ data

interpretation for clinical practice?

A ‘Virtus stat in medio’ Compromise

HR 0.76 (0.59, 0.98) HR 1.20 (0.91, 1.59)

ASCO 2008 Update

AR=761/1861 (41%)!!

Conducting a phase III trial in the traditional way with broad eligibility

• May result in a false negative trial● Unless a sufficiently large proportion of the patients have

tumors driven by the targeted pathway

• May result in a positive trial ● With overall results driven by a subset of patients ● Resulting in subsequent treatment of many patients who do

not benefit

• May provide conflicting results by subgroup analysis mis-interpretation

Modified - Courtesy of Simon R, 2008

Example: if you test 10 subgroups, your chance is:

~40%

~9%

~2%

Biomarker Research Strategy

How to deal with the target…

1. 'Randomize all'design– Biomarker-Stratified Design

2. 'Targeted'design– Enrichment Design

3. 'Strategy'('customized') design– Biomarker-Strategy Design

4. Combo

‘Randomize-All’ Design

1

Courtesy of Billingham C, 2008

‘Targeted’ Design

2

‘Customized’ Design

3

4

4

Which ways to go forward?1. Development of

prospective validation of biomarker-driven drugs in the EARLY PHASES

2. Development of an easier/rapid analytical and statistical methodology to ‘push’ drugs from the early phases to clinical practice

Courtesy of Simon R, 2008

Using Genomics in the Design of Phase III Clinical Trials• Prospectively specified analysis plans for randomized phase III studies are essential to

achieve reliable results

● Biomarker analysis does not mean exploratory analysis except in developmental studies

● Prospective analysis of previously conducted trials can provide reliable conclusions

• Moving from correlative science to predictive oncology requires paradigm changes in some aspects of design and analysis of clinical trials

• DEVELOPMENT of ‘ADAPTATIVE DESIGNS’ for clinical trials, based on molecular features, and adjusted on biases in methodology of markers determination, etc.

The most quoted paper in the last (& Forthcoming) 10yrs.............

Conclusions• Drug (and patient) success depends on extensive pre-

clinical and early clinical modeling● Depends on good science…!

• Phase II remains CRUCIAL to targeted drug development● explore surrogate biomarkers and potential selection

markers.• Phase II should be hypothesis-generating and should

signal:● to progress to Phase III● to go back to the lab!

How it should be…..• Drugs coming from those positive early with

newest adaptative design (ex.: Phase II R with alpha = 0.20), after more realistic basic hypotheses:● ‘Tailored’ on a specific molecular feature● Actual ‘BENCH to BEDSIDE’ medicine

• If you have better early studies, few drugs will enter phase III● Increased chance to win over standard!

• The following phase III trial (always mandatory), will:●Be a ‘superiority trial’●Test big differences,

• less patient to be enrolled• shorter time to be completed

●Your chances to publish on NEJM will increase!

…..How it must be!

‘……Remember, with great power (i.e. Phase III) comes great responsibility (i.e. treating

patients) ...’

[Uncle Ben, (to) Spiderman I, 2002]